Numerous physiological functions involve the transport of water or solutes across a semi-permeable membrane. The driving force for such transport is a concentration gradient that exists across the membrane. Assuming that the pores of the membrane are large enough to accommodate the solutes, solutes will diffuse from a side of the membrane where the solute is more concentrated to a side of the membrane where the solute is less concentrated, in order to achieve a dynamic equilibrium. Diffusion is a type of passive transport as no energy is expended to make the process happen. Osmosis is a special case of passive transport in which water moves across a selectively permeable membrane from a hypotonic solution to a hypertonic solution. As both of these processes are dependent on the concentration of solutes, diffusion and osmosis may be controlled by adding a diffusion or osmotic agent to a system. Many treatments for conditions relating to, for example, electrolyte imbalances, acid-base imbalances, blood pressure, waste removal and build up of fluid involve removing solutes or water from a bodily fluid through the use of a diffusion agent and/or an osmotic agent, either in vivo or ex vivo, or involve using an osmotic agent to induce dehydration.
In cases where such imbalances arise as a result of reduced kidney function, patients have two options for renal replacement therapy, dialysis and kidney transplant. Two forms of dialysis are used in clinical practice: hemodialysis (“HD”) and peritoneal dialysis (“PD”). PD may be used in conjunction with HD with rates of PD comprising 0-70% of Canadian national dialysis programs (Grassmann, A., et al., (2005) Nephrol. Dial. Transplant 20(12): 2587-2593). Epidemiological data has demonstrated non-inferior outcomes for PD patients compared to their hospital-based HD counterparts (Vonesh, E. F., et al., (2006) Kidney Int. Suppl. 103: S3-S11).
HD uses an external apparatus to clean a patient's blood through a vascular circuit, while PD uses the patient's own abdominal lining, the peritoneal membrane, as a filter for waste excretion. HD is usually performed in a dialysis facility three times per week for three to four hours, where trained nurses and technicians carry out the prescribed treatment using a dialysis machine under the direction of a physician. After receiving training by dialysis facility staff, patients administer PD multiple times daily at home, which allows them to live more independently; however, PD requires the regular upkeep and maintenance of an indwelling PD catheter and supplies. This increased autonomy has translated into increased quality-of-life and therapy satisfaction scores for PD patients when compared to HD patients (Theofilou, P. (2011) J. Clin. Med. Res. 3(3): 132-138; Rubin, H. R., et al., (2004) J. Am. Med. Assoc. 291(6):697-703). PD has also been shown to be less expensive than HD on the order of tens of thousands of dollars per patient-year (Sharif, A., Baboolal, K., (2011) Perit. Dial. Int. Suppl. 2: S58-S62), and has therefore gained increasing preference in developing countries with limited healthcare budget, healthcare infrastructure, and access to health services (Nayak, K. S., et al., (2009) Contrib. Nephrol. 163: 270-277).
In addition, many studies have demonstrated better preserved residual renal function in PD patients (Marron, B., et al., (2008) Kidney Int. Suppl. 108: S42-S51; Lang, S. M., et al., (2001) Petit. Dial. Int. 21(1): 52-57). This directly translates into better handling of phosphate, salt and fluid and results in less dietary restrictions and improved quality-of-life for PD patients (Marron, B., et al., (2008) Kidney Int. Suppl. 108: S42-S51). Patients also demonstrate reduced incidence of anemia and left ventricular hypertrophy (Marron, B., et al., (2008) Kidney Int. Suppl. 108: S42-S51). This may explain why the incidence of heart failure hospitalization is reduced in PD patients compared with matched HD counterparts (Trespalacios, F. C., et al., (2003) Am. J. Kidney Dis. 41(6): 1267-1277).
Moreover, there is increasing evidence that PD is a more suitable bridge to renal transplantation than HD for patients with end-stage renal disease. Patients on PD may have lower incidences of hepatitis infection and thus fewer complications with subsequent immunosuppressive therapy (Yang, Q., et al., (2009) Clin. Nephrol. 72(1): 62-68). Graft outcomes appear to be improved with PD patients compared to matched HD controls that undergo renal transplant (Sezer, S., et al., (2011) Transplant Proc. 43(2): 485-487; Domenici, A., et al., (2011) Int. J. Nephrol. 2011: 204216; Bleyer, A. J., et al., (1999) J. Am. Soc. Nephrol. 10(1): 154-159; Goldfarb-Rumyantzev, A. S., et al., (2005) Am. J. Kidney Dis. 46(3): 537-549). Patients on PD will also have preserved vascular access for future dialysis in the event of graft failure. Therefore, there is incentive to initiate PD first and attempt to offer PD as the exclusive pre-transplant dialysis modality for adult and pediatric patients awaiting timely renal transplant.
Current PD solutions may be prepared using a high concentration of glucose as a primary osmotic agent. This glucose may produce systemic and locoregional health complications for PD patients. Daily exposure to glucose can cause hyperglycemia, hyperinsulinemia, obesity and exacerbation of diabetes. Moreover, exposure to glucose and glucose degradation products has been shown to directly damage the peritoneal membrane leading to abnormal mesothelial transformation, maladaptive angiogenesis and ultrafiltration failure (UFF). This phenomenon is characterized clinically by increased membrane permeability to small solutes, rapid absorption of intraperitoneal glucose, and inadequate fluid removal during PD. UFF, and thus inadequate fluid removal with PD, is one of the main reasons patients will stop PD and require transition to HD. Furthermore, the use of glucose may be associated with increasing the susceptibility of PD patients to the development of peritonitis, the decline of residual kidney function, and the loss of peritoneal membrane function. Reducing peritoneal inflammation is likely to delay UFF and prolong the time patients spend on PD. Minimizing glucose exposure may prevent some of the metabolic complications associated with PD. Improving locoregional host defense and reducing the glucose concentration in the peritoneum may also lead to decreased rates of aseptic and bacterial peritonitis.
Icodextrin, a large glucose-based polymer, has been designed to mitigate many of the problems encountered with long-term glucose exposure. Indeed, clinical trials have shown improved metabolic parameters in patients prescribed PD regimens containing icodextrin despite the elevated levels of blood maltose seen with icodextrin therapy. Notably, cell count in the peritoneal effluent of PD patients is significantly higher with icodextrin than glucose, indicating the potential ongoing role of icodextrin in peritoneal inflammation. The main clinical role of icodextrin has been in patients with established UFF when glucose can no longer remove water from the body. Due to its large size, icodextrin will remain intraperitoneal for longer and therefore achieve more reliable ultrafiltration compared to glucose. Yet, icodextrin exists in the dialysis solution as a polydispersed molecule of varying molecular weights and loses osmotic efficiency compared to the same concentration of monodispersed polymer. Moreover, due to the relatively slow fluid kinetics of icodextrin, it can only be used once daily for an extended dwell. There still appears to be a need for alternative biocompatible PD solutions that can be used for multiple dwells per day.
The pH of the PD solution may also play a role in the biocompatibility of the PD solution. PD solutions having a physiological pH may prevent the peritoneal inflammation that eventually leads to peritoneal membrane failure. Conventional PD solutions are typically acidic. Therefore, developing a PD solution with a physiological pH may prolong the viability of the peritoneal membrane.